The pathophysiological role of the immunoproteasome in atherosclerosis

免疫蛋白酶体在动脉粥样硬化中的病理生理作用

基本信息

批准号：
8634347
负责人：
Joerg Herrmann
金额：
$ 12.7万
依托单位：
MAYO CLINIC ROCHESTER
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-01-01 至 2018-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8634347
关键词：
Accounting Acute myocardial infarction Advanced Development American Apolipoprotein E Area Arterial Fatty Streak Atherogenic Diet Atherosclerosis Bone Marrow Bone Marrow Transplantation CD4 Positive T Lymphocytes CD8B1 gene Cardiovascular Diseases Carotid Artery Plaques Cause of Death Cell physiology Cells Cessation of life Chronic Colitis Cytokine Signaling Data Dendritic Cells Development Diagnostic Diet Disease Disease Pathway Endothelial Cells Experimental Models Fatty acid glycerol esters Foam Cells Functional disorder Genetic Goals Image In Vitro Individual Inflammation Inflammatory Injury Interferon Type II Knowledge Medical Mission Modeling Molecular Profiling Morbidity - disease rate Mus Myocardial Infarction Outcome Patient Care Patients Pattern Population Process Public Health Research Rheumatoid Arthritis Risk Factors Role Rupture Shoulder Signal Transduction Societies Structure T-Lymphocyte Therapeutic Tissues Up-Regulation Work base cardiovascular risk factor cell transformation cytokine expectation human disease improved in vivo inhibitor/antagonist innovation insight macrophage monocyte mortality novel prevent prognostic public health relevance research study response theories

项目摘要

DESCRIPTION (provided by applicant): Atherosclerosis continues to progress structurally in one third of patients on optimal medical therapy and every 30 seconds still, an American will have an acute myocardial infarction, and every minute, one will die from one. These data point to the existence of significant gaps in our understanding of this disease process. The long- term goal of the current line of research is, thus, to identify new disease pathways and treatments in atherosclerosis. Studies in other chronic inflammatory diseases have pointed out a phenomenal reduction in tissue inflammation and injury by specific inhibition of the immunoproteasome. Our own preliminary studies demonstrate the expression of immunoproteasome subunits in the shoulder areas of complicated plaques. Guided by these data, the objective of the current application is to determine the expression pattern and pathophysiological significance of the immunoproteasome in an established murine model of atherosclerosis. Our central hypothesis is that the immunoproteasome contributes to the development of advanced atherosclerotic plaques in mice primarily via its activity in bone marrow-derived inflammatory cells. The rationale for these studies is that identification of the role of the immunoproteasome in atherosclerosis will provide further insight into disease mechanisms and novel therapy options. This proposal pursues three specific aims: 1) Determine a) the expression profile of the immunoproteasome in atherosclerosis in apolipoprotein E-deficient (apoE -/-) mice on a high fat diet and b) the effect and mechanisms of action of pharmacological immunoproteasome inhibition in this atherosclerosis model; 2) Determine the leading cell origin of immunoproteasome activity in atherosclerosis; and 3) Determine the role of the immunoproteasome in interferon gamma cytokine signaling on a) endothelial cell function and b) macrophage plasticity. Under aim 1a, apoE-/- mice will be subjected to a high fat diet and the expression profile of the immunoproteasome over the course of atherosclerosis development will be defined. Under aim 1b, apoE-/- mice will be treated with a specific immunoproteasome inhibitor started with (progression model) or after (regression model) the start of the high fat dit. Under aim 2, chimeric bone marrow transplantation experiments will be performed to assess the influence of genetic deficiencies in immunoproteasome subunits in bone marrow-derived inflammatory cells and specifically in CD+ and CD8+ T-cells on experimental atherosclerosis. Under aim 3, the functional significance of the immunoproteasome for interferon gamma signaling in endothelial cells and macrophages will be studied in vitro and in vivo. This proposal is innovative as it will provide first data in atherosclerosis on an increasingly recognized important regulator of inflammation: the immunoproteasome. This proposal is significant because it has the potential to vertically advance our scientific understanding of the atherosclerotic disease process. Ultimately, this is to reduce the burden of atherosclerosis on the individual and society.

描述（由申请人提供）：三分之一接受最佳药物治疗的患者的动脉粥样硬化继续发生结构性进展，每 30 秒就有一名美国人患上急性心肌梗塞，每分钟就有一人死于急性心肌梗塞。这些数据表明我们对这种疾病过程的理解存在重大差距。因此，当前研究的长期目标是确定动脉粥样硬化的新疾病途径和治疗方法。对其他慢性炎症疾病的研究指出，通过特异性抑制免疫蛋白酶体，可显着减少组织炎症和损伤。我们自己的初步研究证明了复杂斑块肩部区域中免疫蛋白酶体亚基的表达。在这些数据的指导下，当前应用的目的是确定免疫蛋白酶体在已建立的动脉粥样硬化小鼠模型中的表达模式和病理生理学意义。我们的中心假设是，免疫蛋白酶体主要通过其在骨髓源性炎症细胞中的活性，促进小鼠晚期动脉粥样硬化斑块的形成。这些研究的基本原理是，鉴定免疫蛋白酶体在动脉粥样硬化中的作用将有助于进一步了解疾病机制和新的治疗选择。该提案追求三个具体目标：1) 确定 a) 高脂饮食的载脂蛋白 E 缺陷 (apoE -/-) 小鼠动脉粥样硬化中免疫蛋白酶体的表达谱，以及 b) 药理学免疫蛋白酶体抑制的作用和机制在这个动脉粥样硬化模型中； 2) 确定动脉粥样硬化中免疫蛋白酶体活性的主导细胞起源； 3) 确定免疫蛋白酶体在干扰素 γ 细胞因子信号转导中对 a) 内皮细胞功能和 b) 巨噬细胞可塑性的作用。在目标 1a 下，apoE-/- 小鼠将接受高脂肪饮食，并且将确定动脉粥样硬化发展过程中免疫蛋白酶体的表达谱。在目标 1b 下，apoE-/- 小鼠将在高脂肪饮食开始时（进展模型）或之后（回归模型）接受特异性免疫蛋白酶体抑制剂治疗。在目标2下，将进行嵌合骨髓移植实验，以评估骨髓源性炎症细胞、特别是CD+和CD8+ T细胞中免疫蛋白酶体亚基遗传缺陷对实验性动脉粥样硬化的影响。在目标 3 下，将在体外和体内研究免疫蛋白酶体对内皮细胞和巨噬细胞中干扰素 γ 信号传导的功能意义。该提案具有创新性，因为它将提供有关动脉粥样硬化的第一个数据，该数据涉及日益被认可的重要炎症调节因子：免疫蛋白酶体。这项提议意义重大，因为它有可能垂直推进我们对动脉粥样硬化疾病过程的科学理解。最终，这是为了减轻动脉粥样硬化对个人和社会的负担。